J-lower alkoxy-x-phenyloxy-ix-hydroxy-



United States Patent 3,166,559 3-LOWER ALKOXY-4-PHENYLOXY-14-HYDROXY- N-METHY LMORPHINAN S Yoshiro Sawa and Shin Maeda, Hyogo Prefecture, and Naoki Tsuzi, Osaka Prefecture, Japan, assignors to Shionogi & Co., Ltd., Osaka, Japan No Drawing. Filed Apr. 4, 1963, Ser. No. 270,555 Claims priority, application Japan, Apr. 9, 1962,

37/ 14,252 2 Claims. (Cl. 260-285) The present invention relates to a process for hydrogenating unsaturated morphinans and the saturated morphinans produced thereby.

In the term morphinan herein employed, there are included all the compounds having a fundamental structure representable by the following plane formula:

3-methoxy-N-methyl-M-morphinan, 3-rnethoxy-N-methyl- A -rnorphinan, 3-met-hoxy N methyLN-morphinan, 3- methoxy-14-hydroxy-N-methyl-A -morphinan, 3-ethoxy- N-m-ethyl-A -morphinan, 3-methoxy-4-phenyloxy-N-methyl-M-morphinan, 3-rnethoxy-4-phenyloxy-14-hydroxy-N- methyl-M-morphinan, etc.'

According to the process of the present invention, the starting unsaturated morphinan (I) is subjected to hydrogenation to produce the saturated morphinan of Formula II. Although various conventional hydrogenation procedures can be adopted for attaining the object, the application of catalytic hydrogenation is preferred. For instance, the hydrogenation reaction may be effected by treating the unsaturated morphinan (I) with hydrogen in the presence of a catalyst such as platinum catalyst (e.g. platinum, platinum dioxide, platinum black, platinum-carbon), palladium catalyst (e.g. palladium, palladium monoxide, palladium black, palladium carbon, palladium-strontium carbonate, palladium-barium sulfate) and nickel catalyst (e.g. Raney nickel, Urushibara nickel) in an inert solvent medium (e.g. water, methanol, ethaand morphinan wherein R represents a hydrogen atom or a lower alkyl 7 group (e.g. methyl, ethyl, propyl), R' represents a hydrogen atom, an aryloxy group (e.g. phenyloxy, naphthyloxy) or a subsituted aryloxy group (e.g. substituted phenyloxy, substituted naphthyloxy) wherein the suhn01, ether, tetrahydrofuran, dioxane, benzene, acetic acid), usually at room temperature (15 to 30 C.) under atmospheric pressure.

The saturated morphinan (II) occurs in optically active form as well as in racemic mixture and these are all within the scope of the present invention. Specific examples of the saturated morphinan (11) include 3-hydroxy-N-methylmorphinan, 3,14-dihydroxy-N-methylmorphinan, 3-methoxy-N-methylmorphinan, 3-methoxy-14- hydroxy-N-methylmorphinan, 3-ethoxy-N-methylmorphinan, 3-methoxy-4-phenyloxy-N-methylmorphinan, 3-methoxy-4-phenyloxy-14-hydroxy-N-methylmorphinan, etc.

The saturated morphinan (II) for-ms acid addition salts with organic and inorganic acids. Illustrative acid addition salts include the hydrohalide (e.g. hydrochloride, hydrobromide, hydroiodide), sulfate, phosphate, nitrate, tartrate, salicylate, benzoate, malate, citrate, acetate, etc.

The saturated morphinan (II) and acid addition salts thereof exhibit various pharmacological activity such as analgesic activity and antitussive activity. For instance, the analgesic activity, antiitussive activity and toxicity of some compounds according to the present invention are shown in the following table:

TABLE Analgesic Antitnssive Toxicity Compound activity activity (LD50,

(+)-3-Hydroxy-N-methyl-morphinan (eis) 0.1 1. 2 62. 1 (-)-3-Hydrexy-N-methy1-mor phinan (cis) 3. 9 7. 0 23. 4 (5:)-3-Hydroxy-N-methyl-morphinan (cis) 2.9 3. 8 51.0 (+)-3-Hydroxy-N-methyl-morphinan (trans) 2.0 25.0 (-)-3-Hydroxy-N-methyl-morphinan (trans 2. 8 31. 3 (+)-3-Methoxy-N-methyl morphinan (eis) hydrobromide 1. 1 51. 5 ()-3-Methoxy-N-methyl-morphinan (eis) hydrobromide 0. 6 2. 5 42. 3 (5:)-3-Methoxy-N-methy1-morphinan (eis) hydrobromide 0.6 2. 4 45. 7 (-)-3-Ethoxy-N-methyl-morphinan (eis) phosphate 0.6 2. 5 52.6 ()-3,14=-Dihydroxy-N-methylmorphinan (cis) 1. 5 3.8 63. 7 (-)-3-Methoxy-14-hydroxy-N- methylmorphinan (eis) 0.5 3. 4 43. 1

Norn.--The analgle ie activity was observed by the ,Haiiner-Hesse method [Hessez Arc exp. Path. u. Pharm., vol. 158, p. 233 (1930)] in mice and is shown as the eiiective ratio to morphine, the value of which is expressed as 1. The antitussive activity was observed by the Winter method [Winter et; al.: J. Exper. Med., vol. 101, p. 17 (1955)] in guinea. pigs and is shown as the effective ratio to codeine, the value of which is expressed as 1. The toxicity was tested by intravenous administration of the tested compound to mice.

Other saturated morphinans (II) show the similar activities. Accordingly, they are useful as analgesic and/or antitussive agents.

Practical and presentlypreferred embodiments of the present invention are illustrated by the following examples. In the examples, mg.=milligram(s), g.=gram(s), ml.= mi1lilitre(s) and C.=degrees centigrade. Other abbreviations have conventional meanings.

Example 1 Preparation of 3-methoxy-N-methylmorphinan (cis):

cn o 0x 0 N-CH3 w NNQH To a solution of a mixture of ()-3-methoxy-N-methy1- A -morphinan (cis) and ()-3-methoxy-N-methyl-A morphinan (cis) (200 mg.) in methanol (18 ml.), there is added platinum dioxide (70 mg), and the resultant mixture is shaken at room temperature (15 to C.) in hydrogen stream. After absorption of hydrogen (31 ml.), the reaction mixture is filtered to separate the catalyst and distilled to remove the solvent. The residue (203 mg.) is crystallized from ether to give ()-3-meth0xy-N- methylmorphinan (cis) as crystals melting at 108 to 110 C.

The starting material of this example, (-)-3-methoxy- N-methyl-A -morphinan (cis), is prepared from desoxydihydrothebainone [Sawa et al.: Tethahedron, vol. 15, p. 154 (1961)] according to the following scheme:

CH Q

/ Reduction using platinum dioxide. 3

N-CH J 3 O CH O Sulfonylation. with p-toluenesulfony]. chloride and pyridine. I

Ii -CH CH O Deacidation with.

collidine. M

N-CH

Example 2 Preparation of (-)-3-methoxy-N-methylmorphinan (trans):

Y... 1. CH

To a solution of ()-3-methoxy-N-methyl-A -morphinan (trans) (98 mg.) in methanol (10 ml.), there is added platinum dioxide (30 mg.), and the resultant mixture is shaken at room temperature (15 to 30 C.) in hydrogen stream. After absorption of hydrogen (7.2 ml.), the reaction mixture is filtered to separate the catalyst and distilled to remove the solvent. The thus obtained crude ()-3-methoxy-N-methylmorphinan (trans) (92 mg.) is treated with picric acid in ethanol and crystallized from ethanol to give ()-3-methoxy N methylmorphinan (trans) picrate as crystals melting at 212 to 213 C.

Analysis.-Calcd. for C18H250N'C3H307N3: C, 57.54; H, 5.63; N, 11.19. Found: C, 57.55; H, 5.93; N, 11.53.

The starting material of this example, )-3-methoxy- N-methyl-A' morphinan (trans), is prepared from 3,6-dimeth0Xy-N-methyl-A -morphinan (cis) [Sawa et a1.: Tetrahedron, vol. 15, p. 154 (1961)] according to the following scheme:

CH O

Treatment with 10 7: hydrochloric acid. 5 CH hydrate li -CH CH O and

Example 3 Preparation of 3-methoxy-N-methylmorphinan (cis):

To a solution of (-)-3-methoxy-N-methyl-A' -morphinan (cis) (96 mg.) in methanol (10 ml.), there is added platinum dioxide (30 mg), and the resultant mixture is shaken at room temperature to 30 C.) in hydrogen stream. After absorption of hydrogen (6.5 ml.), the reaction mixture is filtered to separate the catalyst and distilled to remove the solvent. The residue is crystallized from ether to give ()-3-mcthoxy-N-methylmorphinan (cis) (93 mg.) as crystals melting at 107.5 to 109 C.

The starting material of this example, ()-3-methoxy- N-methyl-A' -morphinan (cis), is prepared from ()-3- methoxy-6-oxo-N-methyl-A' -morphinan (cis) [cf. Example 2 of this specification] according to the following scheme:

Huang-Minlon reduction. with briethylerie glycol, potassium hydroxide and hydrazine hydrate. W

Iii-CH V Example4 Preparation of (+)-3-methoxy-4-phenyloxy-N-methylmorphinan (cis):

To a solution of (+)-3-methoxy-4-phenyloxy-N-methyl-A -morphinan (cis) (1.2 g.) in glacial acetic acid (50 ml), there is added platinum dioxide (50 mg), and the resultant mixture is shaken at room temperature (15 to 30 C.) in hydrogen stream. After absorption of hydrogen (62 ml.), the reaction mixture is filtered to separate the catalyst and distilled to remove the solvent.

' The residue (1.2 g.) is crystallized from petroleum ether to give (+)-3-rnethoxy-4-phenyloxy-N-methylmorphinan (cis) as crystals melting at 95 to 96 C. [001 +9.5 (ethanol).

Analysis.-Ca1cd. for C H O N: C, 79.30; H, 8.04; N, 3.85. Found: C, 79.29; H, 8.06; N, 3.76.

The starting material of this example, (+)-3-methoxy- 4-pheny1oxy-N-methyl-A -morphinan (cis), is prepared from sinomenine phenyl ether [Sawa et al.: Tetrahedron, vol. 15, p. 144 (1961)] according to the following scheme:

(ll-I 0 Clemmensen re- C H O duction with amalgamated zinc and hydrochloric 3 fi f Example 5 Preparation of 3 methoxy-N-methylmorphinan (cis):

' (II-I 0 To a solution of (+)-3-methoxy-N-methy1-A -morphinan (cis) (180 mg.) in glacial acetic acid (6 m1.), there is added platinum dioxide (10 mg), and the resultant mixture is shaken at room temperature 15 to 30 C.) in hydrogen stream. After absorption of hydrogen (18 ml.), the reaction mixture is filtered to separate the catalyst and distilled to remove the solvent. The residue 180 mg.) is crystallized from petroleum ether to give (+)-3-methoxy-N-methylmorphinan (cis) as crystals melting at to 108 C.

The starting material of this example, (+)-3-methoxy- N-methyl-A -morphinan (cis), is prepared from desoxysinomenine [Sawa et al.: Tetrahedromyol. 15, p. 144 (1961)] according to the following scheme CH O Clemmensen reduction with amalgamated zinc and hydrochloric NWCH acid.

7 Example 6 Preparation of (-)3methoxy-4-phenyloxy-N-methylmorphinan (cis):

CH CH 3 C H O N-CH Ne-CH To a solution of ()3methoxy-4-phenyloxy-N-methyl-N-morphinan (cis) (28 mg.) in ethanol 10 ml.) there is added platinum dioxide mg.), and the resultant mixture is shaken at room temperature (15 to 30 C.) in hydrogen stream. After absorption of hydrogen (4.4 ml.), the reaction mixture is filtered to separate the catalyst and distilled to remove the solvent. The thus obtained crude (-)3methoxy-4-phenyloxy-N-methylmorphinan (cis) (24 mg.) is treated with methyl iodide to give the methiodide as crystals melting at 236.5 to 237 .5 C.

The starting material of this example, ()-3-methoxy- 4-phenyloxy-N-methyl-A' -morphinan (cis), is prepared from 3,6 dimethoxy-4-phenyloxy-N-methyl-A morphinan (cis) [Sawa et al.: Tetrahedron, vol. 15, p. 154 (1961)] according to the following scheme:

CHSO reatment with C H O 10 iihydrochlorio 6 5 acid.

. N-CH Huang-Minlon reduction with Preparation of 3methoxy-N-methylmorphinan (cis):

CHO

To a solution of ()-3methoxy-N-methyl-A -morphinan (cis) (50 mg.) in ethanol (15 ml.), there is added platinum dioxide (30 mg.), and the resultant mixture is shaken at room temperature (15 to 30 C.) in hydrogen stream. After absorption ofhydrogen (9.8 ml.), the reaction mixture is evaporated to remove the solvent. The residue is dissolved in ether and filtered to separate the insoluble catalyst. The filtrate is evaporated and crystallized from ethanol to give ()-3-methoxy-N-methylmorphinan (cis) (48 mg.) as crystals melting at 108 to 109 C.

The starting material of this example, ()-3-methoxy- N-methyl-A -morphinan (cis), is prepared from ()-3- methoxy-6-oxoN-methyl-N-morphinan (cis) [of Example 2 of this specification] according to the following scheme:

Dehydration with pyridine hydro-- chloride.

N-CH

N-CH

Example 8 Preparation of 3 hydroxy-N-methylmorphinan (cis):

..ca I I 3 To a solution of ()3hydroxy-N-methyl-A -mor- I phinan (cis) mg.) in ethanol (10 ml.), there is added platinum dioxide (30 mg.), and the resultant mixture is shaken at room temperature (15 to 30 C.) in hydrogen stream. After absorption of hydrogen (27.5 ml.), the

reaction mixture is filtered to separate the catalyst and distilled to remove the solvent. The residue is crsytallized from tert. amyl alcohol to give ()-3-hydroxy-N-methylmorphinan (cis) (41 mg.) as crystals melting at 198 to 199 C.

The starting material of this example, ()-3-hydroxy- N-methyl-A -morphinan (cis), is prepared from ()-3- methoxy 6 oxo-N-methyl-N-morphinan (cis) [cf. Ex-

ample 2 of this specification] according to the following scheme:

Hydrolysis with: hydrobromic acid. W

N--CH Reduction wi th sodium borohydride.

Dehydration with pyridine hydrochloride.

Example 9 Preparation of )-3-methoxy N methylmorphinan (trans) CH O To a solution of ()-3-methoxy N methyl-A' -morphinan (trans) (98 mg.) in methanol (10 ml.), there is added platinum dioxide (30 mg.), and the resultant mixture is shaken at room temperature to 30 C.) in hydrogen stream. After absorption of hydrogen (7.2 ml.), the reaction mixture is filtered to separate the catalyst and distilled to remove the solvent. The thus-obtained crude ()-3-methoxy N methylmorphinan (trans) (92 mg.) is treated with picric acid in ethanol and crystallized from ethanol to give the picrate as crystals melting at 212 to 213 C.

Analysis.Calcd. for C13H25ON'C6H3O7N3I C, 57.54; H, 5.63; N, 11.19. Found: C, 57.55; H, 5.93; N, 11.53.

'10 The starting material of this example, ()-3-methoxy- N-methyl-A' -morphinan (trans), is prepared from ()-3- methoxy-6-oxo N methyl-A' -morphinan (cis) [cf. EX- ample 2 of this specification] according to the following scheme:

Huang-Minion reduc'tion with briefchylene glycol, potassium hydroxide and hydrazine hydrate.

N-ICH3 CHO CH O

N-CH

Example 10 Preparation of ()-3-meth0xy 4 phenyloxy-l i-hydroxy-N-methylmorphinan (cis):

To a solution of (')-3-methoxy-4-phenyloxy-14-hydroxy-N-methyl A morphinan (cis) (300 mg.) in 10% acetic acid (6 ml.), there is added platinum dioxide (15 mg.), and the resultant mixture is shaken at room temperature 15 to 30 C.) in hydrogen stream. After absorption of hydrogen (25 ml.), the reaction mixture is filtered to separate the catalyst. The filtrate is neutralized with ammonia-water and shaken with dichloromethane. The dichloromethane layer is evaporated and the residue crystallized from ethanol to give ()-3-methoxy-4-phenyloxy-14-hydroxy-N-methylmorphinan (cis) (301 mg.) as crystals melting at 112 to 113 C. [M11324 29.4 (chloroform).

. Analysis.-Calcd. for C H O N: C, 75.96; H, 7.70; N, 3.69. Found C, 75.88; H, 8.05; N, 3.56.

The starting material of this example, (-)-3-methoxy- 4-phenyloxy 14 hydroxy-N-methyl-A -morphinan (cis) is prepared from ()-3-methoxy 4,14 dihydroxy-N- methyl A morphinan (cis) [Sekia Annual Report of Takamine Research Laboratory, vol. 13, p. 67 (1961)] according to the following scheme:

Etherification with bronzebenzene What is claimed is:

1. 3 -lower alk0xy-4-phenyloxy-14-hydroxy-N-methy1- morphinan.

2. )-3-methoxy 4 phenyloxy-14-hydroxy-N-methylmorphinan (cis).

References Cited in the file of this patent UNITED STATES PATENTS Hartung: Ind. and Eng. Chem., vol. 37, pp. 126-127 (1945 TP 1 A58.

Gates et 211.: J. Am.. Chem. Soc. vol 80, pp. 11861194 (1958),QD 1A5. 

1. 3 - LOWER ALKOXY-4-PHENYLOXY-14-HYDROXY-N-METHYLMORPHINAN. 